GLENNIS LOGSDON, PH.D.
I'm a postdoctoral research fellow in Evan Eichler's laboratory at the University of Washington School of Medicine Department of Genome Sciences, where I study the sequence, variation, evolution, and function of human centromeres using computational, phylogenetic, and cell biological approaches.
I'm an NIH K99-funded postdoctoral research fellow at the University of Washington School of Medicine, where I study the sequence, structure, and evolution of human centromeric regions under the guidance of Dr. Evan Eichler.
I previously obtained my Ph.D. in Biochemistry and Molecular Biophysics from the University of Pennsylvania Perelman School of Medicine in 2018, where I studied centromere establishment on human artificial chromosomes under the guidance of Dr. Ben Black.
I also obtained my B.A. in Biochemistry from the University of Pennsylvania in 2011, where I studied telomeric noncoding RNAs in budding yeast, under the guidance of Dr. Brad Johnson.
As I transition to independence, I hope to apply my understanding of human centromere sequence, variation, and function to build new, more efficient centromeres on human artificial chromosomes that can be used to better understand our genome and treat human diseases.
Centromere sequence, structure, and evolution
I study a specialized region on each chromosome known as the centromere, which is an essential locus that that mediates the segregation of chromosomes during cell division. In humans, centromeres are comprised of near-identical repeats known as alpha-satellite, which are 171 bp long and organized in multi-megabase arrays on each chromosome. Because of the repetitive nature of these regions, centromeres have posed an enormous challenge to standard short-read sequencing and assembly methods, and consequently, all centromeres have remained unresolved in the human reference genome for the past twenty years. During my postdoctoral training, I developed a novel computation assembly method that combines two long-read sequencing technologies, Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT), to generate the first complete sequence of a centromere on a human autosome, chromosome 8. I also applied this method to resolve every remaining gap on chromosome 8, thereby generating the first telomere-to-telomere sequence of a human autosomal chromosome (Logsdon et al., Nature, 2021).
The sequence, structure, epigenetic, and evolutionary map of the human chromosome 8 centromere. This centromere consists of a 2.08 megabasepair (Mbp) D8Z2 alpha-satellite higher-order repeat (HOR) array flanked by blocks of monomeric/divergent alpha-satellite. The D8Z2 HOR array is heavily methylated, except for a small, 73 kbp region that is hypomethylated. This hypomethylated region is centered within the 632 kbp centromeric chromatin domain, marked by the presence of the histone H3 variant, CENP-A. A pairwise sequence identity heat map reveals five major evolutionary layers and a mirror symmetry, characteristic of active sequence homogenization within the core of the HOR array. Adapted from Logsdon et al., Nature, 2021.
The sequence, structure, and evolutionary map of the chromosome 8 centromere in chimpanzee, orangutan, and rhesus macaque. All three centromeres have a layered and symmetrical organization, similar to that observed in humans. Adapted from Logsdon et al., Nature, 2021.
Analysis of the structure of the human chromosome 8 centromere revealed that it is comprised of five major evolutionary layers. To better understand the evolution of the chromosome 8 centromere, I generated complete sequence assemblies of the orthologous chromosome 8 centromere in chimpanzee, orangutan, and rhesus macaque, and I used these assemblies to reconstruct the evolutionary history of this centromere over the last 25 million years. I found that each centromere has the same layered and symmetrical organization observed in the human centromere. Additionally, I confirmed that the alpha-satellite HOR structure evolved after apes diverged from Old World Monkeys less than 25 million years ago. Phylogenetic comparisons of the chromosome 8 centromeres revealed that it is evolving at least 2.2.-3.8 times faster than the rest of the human genome and is one of the most rapidly evolving regions identified. These findings support a model of centromere evolution where highly identical alpha-satellite repeats emerge and expand in the core of the centromere, pushing older, more divergent repeats to the edges in an assembly line fashion (Logsdon et al., Nature, 2021).
After resolving the sequence of the chromosome 8 centromere, I worked with the Telomere-to-Telomere (T2T) Consortium to resolve the sequence of all remaining centromeres in the human genome. Working throughout the COVID-19 pandemic, we refined our sequence assembly methods and determined the complete sequence of each centromere for the first time (Altemose, Logsdon et al., Science, 2022). We also determined the first complete sequence of the entire human genome (Nurk et al., Science, 2022). This landmark work was published in a special issue in Science and reported in over 1,000 press releases. Importantly, this work revealed that centromeres are remarkably variable in their size, structure, and organization, even within a single human genome. This hyper-variability may impact the ability of centromeres to accurately segregate chromosomes during cell division. Studies that assess the variation of centromeres among the human population may reveal important roles for centromere sequence, structure, and chromatin organization critical for maintaining genome integrity over time.
The complete sequence of each centromere in the human genome reveals a common organization composed of one or more arrays of highly identical alpha-satellite higher-order repeats (HORs), flanked on either side by divergent and monomeric alpha-satellite repeats that transition into unique sequence on the p- and q-arms. The largest centromeric HOR array resides on chromosome 18 and is 4.97 Mbp long, while the smallest array reside on chromosome 21 and is only 343 kbp long. This ~14.5-fold difference in size highlights the incredible variability among centromeres, even within the same human genome. Studies to determine how centromeres vary among the human population in both healthy and diseased individuals promise to shed light on how variation within these regions impact chromosome stability and lead to cancer, infertility, and congenital birth defects. Adapted from Altemose, Logsdon et al., Science, 2022.
Human artificial chromosomes with unique centromeres
Human artificial chromosomes (HACs) are engineered mini-chromosomes that acquire a functional centromere and are stably maintained in human cells. They have the potential to transform synthetic biology and permit the development of numerous radical developments in medicine because they can be used deliver genes or other DNA elements without integration into the host genome. Despite their utility, HACs are considered difficult to engineer because they typically require repetitive centromeric DNA sequences that can complicate cloning, handling, and their stability in bacterial propagation. Overcoming the barrier of repetitive centromeric DNA would accelerate HAC
Metaphase chromosome spreads containing a non-repetitive human artificial chromosomes (HAC; green). Non-repetitive HACs are able to form a functional centromere (marked by the histone H3 variant CENP-A; red) that ensures their stable propagation in cells for long periods of time. Scale bar = 10 microns.
development for their use in the clinic. During my Ph.D. training, I engineered a new type of HAC that is completely devoid of repetitive DNA. This HAC is comprised of DNA sequence from chromosome 4q21 and is stable in cells for several months. This new type of HAC surmounts barriers that have limited the progress of the construction of a synthetic human genome.
Logsdon GA, et al. The structure, function and evolution of a complete human chromosome 8.
Nature. 2021 April 7. PDF
Logsdon GA and Eichler EE. Mining the gaps of chromosome 8.
Nature. 2021 May 14.. PDF
Logsdon GA, Vollger MR, and Eichler EE. Long-read human genome sequencing and its applications.
Nat Rev Gen. 2020 June 5.. PDF
Altemose N, Logsdon GA, et al.
Complete genomic and epigenetic maps of human centromeres.
Science. 2022 April 1. PDF
Nurk et al. The complete sequence of a human genome.
Science. 2022 April 1. PDF
Logsdon GA, et al. Human artificial chromosomes that bypass centromeric DNA.
Cell.. 2019 July 25. PDF
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Photo credit: Oxford Nanopore Technologies
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